Depression is a high prevalence of mental disorders. At present, the traditional clinical antidepressant drugs are safe and efficacious mainly for cerebral monoamine neurotransmitters in patients with depression, but have main defects of: slow efficacy (taking weeks or even months to have an efficacy in smoothing symptoms), resistance to treatment (treatment-resistant depression) and relapse. Therefore, it is in urgent need of developing a fast-acting antidepressant drug for treatment-resistant depression in clinic.
According to the pathogenesis of depression, and around follow-up adaptive change of nervous system, such as neural plasticity, neurogenesis and hypothalamic-pituitary-adrenal (HPA) axis, now the targets of antidepressant drugs mainly include [Newman D J, Cragg G M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod, 2012, 75(3): 311-335.]: 1) acting on monoaminergic systems (biogenic amines for increasing neurotransmitters in brains of patients with depression: 5-hydroxytryptamine (5-HT); norepinephrine (NE), etc.), e.g. 5-HT selective serotonin reuptake inhibitors (SSRIs), NE serotonin-noradrenalin reuptake inhibitors (SNRIs) and dopamine modulators; 2) acting on glutamate receptors, e.g. NMDA receptor antagonists, AMPA receptor modulators; 3) acting on neuropeptide receptors, e.g. neurokinin (NK) receptor antagonists, corticotropin releasing hormone (CRH) receptor antagonists; 4) acting on glucocorticoid receptors (GR), e.g. glucocorticoid receptor antagonists. However, at present, the traditional clinical antidepressant drugs are safe and efficacious mainly for cerebral monoamine neurotransmitters in patients with depression, but have main defects of slow efficacy (taking weeks or even months to have an efficacy in slowing down symptoms), resistance to treatment (treatment-resistant depression) and relapse. Therefore, it is in urgent need of developing a fast-acting antidepressant drug for treatment-resistant depression in clinic [Mathew S J, Manji H K, Charney D S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 2008: 1-13. 2.] [Cryan J F, OLeary O F. A glutamate pathway to faster-acting antidepressants? Science 2010; 912-914.].
In recent years, the research on antidepressant drugs based on new mechanisms of non-monoaminergic biosystems (beyond monoaminergic systems) has attracted widespread attentions [Berton O, Nestler E J. New approaches to antidepressant drug discovery: beyond monoamines Neurosience 2006; 7:137-151]. Major pharmaceutical enterprises in the world have set off a wave of development of novel antidepressant drugs, and found a large number of novel compounds having antidepressant effects: melatonin receptor agonist agomelatine came into the European markets in 2009, and FDA approved the corticotropin releasing hormone receptor antagonist quetiapine as an antidepressant drug in 2009. Furthermore, many other drugs for treating major depressions, including amino acid neurotransmitter receptor antagonists (e.g., NMDA antagonists), neuropeptide antagonists (CRF-1, NK-1 antagonists), glucocorticoids receptor antagonists (GR antagonists), are approved by FDA in phase II and Ill clinical trials [Meng Xiujun, Qu Lei, Ma Yan et al, Research Progress of Novel Antidepressant Drugs. Chinese Journal of New Drugs 2011; 20: 1766-1774.].
C21 steroids are widely distributed in the plant kingdom, and are especially most widely distributed in Asclepiadaceae plants. With pregnane or its isomers as the basic skeleton, C21 steroids isolated from plants are present in plants mainly in the form of glycoside formed by aglycone and sugar, and glycoside may be hydrolyzed under acidic conditions to secondary glycoside or aglycone. The antidepression effect of plant-derived C21 steroidal glycosides has been reported in literatures in recent years: Chinese patents provide applications of a few plant-derived C21 steroidal glycosides (mixtures) in drugs for treatment and prevention of depression [Application of C21 steroid glycoside in pharmacy CN 1634097A]; a literature reports three antidepressant C21 steroidal glycosides isolated from Cynanchum auriculatum [Yang Q X, Ge Y C, Huang X Y, et. al., Cynanauriculoside C-E, three new antidepressant pregnane glycosides from Cynanchum auriculatum. Phytochemistry Letters 2011; 4:170-175.].